Targeting glucagon pathway may offer a new approach to treating diabetes

April 12, 2012

Maintaining the right level of sugar in the blood is the responsibility not only of insulin, which removes glucose, but also of a hormone called glucagon, which adds glucose.

For decades, treatments for type II have taken aim at , but a new study suggests that a better approach may be to target glucagon's sweetening effect.

The findings were published today in the online edition of .

"What we've found is a way to reduce glucagon's influence on without the side effects of global ," said Ira Tabas, MD, PhD, Richard J. Stock Professor and Vice Chair of Research in the Department of Medicine and professor of Anatomy & Cell Biology (in Physiology and Cellular Biophysics), who led the study with Lale Ozcan, PhD, associate research scientist.

Though glucagon was discovered at the same time as insulin, research on it has languished compared with that of its cousin, and treatments have almost exclusively targeted the latter.

In the last decade, the success of incretins, a new class of drugs for type II diabetes, has sparked a renaissance in glucagon research. When they were first introduced, incretins were known to stimulate insulin secretion. But recent studies show that a significant part of their clinical success can be attributed to previously unsuspected inhibiting effects on glucagon secretion.

The experience with incretin has led to a renewed search for other drugs that act against glucagon, including compounds that block glucagon in the liver, where it acts to free glucose. Drugs that block the glucagon receptor in the liver have been tested, but glucagon has multiple roles, and recent early clinical trials show that it can raise cholesterol and lead to fat accumulation in the liver.

The new study shows how glucagon's effect on glucose could be disrupted without disturbing glucagon's other duties, raising prospects for a safer anti-glucagon diabetes treatment.

Drs. Tabas and Ozcan found that once glucagon binds to its receptor, glucose is fully released only after an enzyme called CaMKII is activated. When activated, CaMKII sends a protein called FoxO1 into the cell nucleus, where it turns on the genes needed for secretion. A related pathway, working in parallel to this one, sends a FoxO1 helper protein into the cell nucleus, as reported in a paper on which Dr. Tabas is a co-author, published online on April 8 in Nature (embargoed until that time).

"Even when their disease is well controlled, most patients with have excess glucagon action, so blocking CaMKII could potentially be a new way to lower blood sugar and better treat the disease," said Dr. Tabas.

When the researchers blocked CaMKII in obese, diabetic mice, the animals' blood sugar went down, with no negative side effects. Instead, cholesterol declined, insulin sensitivity improved, and the liver became less fatty.

"Until now, it has been difficult to block glucagon's effect on blood sugar without interfering with glucagon's other functions," said Dr. Tabas, "but we think CaMKII is different."

Dr. Tabas is now working on the possibility of developing a CaMKII inhibitor to treat diabetes.

Explore further: Researchers discover protein that may represent new target for treating type 1 diabetes

More information: Drs. Ozcan's and Tabas' paper is titled, "Calcium signaling through CaMKII regulates hepatic glucose production in fasting and obesity."

Related Stories

Researchers discover protein that may represent new target for treating type 1 diabetes

January 4, 2012
Researchers at Wake Forest Baptist Medical Center's Institute for Regenerative Medicine and colleagues have discovered a new protein that may play a critical role in how the human body regulates blood sugar levels. Reporting ...

Research reveals hormone action that could lead to treatments for type 2 diabetes

September 30, 2011
(Medical Xpress) -- Researchers at the University of Cincinnati have discovered that the immediate improvement in blood sugar (blood glucose) for those with type 2 diabetes who undergo gastric bypass surgery is related to ...

Study finds molecular switch that controls liver glucose production, may offer target for type II diabetes therapy

April 8, 2012
In their extraordinary quest to decode human metabolism, researchers at the Salk Institute for Biological Studies have discovered a pair of molecules that regulates the liver's production of glucose -- the simple sugar that ...

Recommended for you

Smart mat detects early warning signs of foot ulcers

August 16, 2017
While completing his residency in anesthesiology at Massachusetts General Hospital in the mid-2000s, Jon Bloom saw his fair share of foot amputations among patients with diabetes. The culprit: infected foot ulcers.

The best place to treat type 1 diabetes might be just under your skin

August 14, 2017
A group of U of T researchers have demonstrated that the space under our skin might be an optimal location to treat type 1 diabetes (T1D).

New measure of insulin-making cells could gauge diabetes progression, treatment

August 10, 2017
Researchers at the University of Wisconsin-Madison have developed a new measurement for the volume and activity of beta cells, the source of the sugar-regulating hormone insulin.

Pioneering immunotherapy shows promise in type 1 diabetes

August 9, 2017
It may be possible to 'retrain' the immune system to slow the progression of type 1 diabetes, according to results of a clinical trial published today in the journal Science Translational Medicine.

Online team-based game helps patients with diabetes lower blood glucose

August 8, 2017
Researchers from Brigham and Women's Hospital and the Veterans Affairs Boston Healthcare System have found that an online, team-based game designed to teach patients about diabetes self-management had a sustained and meaningful ...

Oxidative stress biomarkers don't always signal diabetes risk

August 7, 2017
High levels of compounds found in the body that are commonly associated with oxidative damage may actually be a good sign for some people, according to a recent review of multiple human studies led by an epidemiologist at ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.